3050 Background: With standard assays (Limit of Detection [LoD95] at or >100 PPM), most patients with ER+/HER2- mBC show ctDNA "clearance" within a few weeks after initiating first- line AI+CDK4/6i, with ctDNA becoming detectable again only at or shortly before progression. To gain a more comprehensive view of ctDNA kinetics in response to therapy, we analyzed serial plasma samples from PADA-1 using a tumor-informed assay with a 100-1,000-fold higher sensitivity (LoD95 <10PPM). Methods: PADA-1 allowed the collection of plasma at baseline and every two months during first-line AI+palbociclib (PAL). A total of 489 serial plasma samples from 45 patients in PADA-1 were analyzed using an ultrasensitive structural variant-based ctDNA assay. WGS was performed on tumor material from archival primary or metastatic biopsies, and personalized multiplex dPCR assays tracking up to 16 somatic structural variants were used for ctDNA monitoring. Results: At baseline, before AI+PAL start, ctDNA was detected in N=40/41 evaluable patients (98%). ctDNA remained detectable in 381/489 (78%) samples during therapy. ctDNA was persistently detectable and quantifiable (i.e. detected at all timepoints) throughout first-line therapy in most initially positive patients (24/40, 60%). With this ultra-sensitive assay, we report, for the first time, that ctDNA follows a recurrent kinetic pattern: (1) a steep decrease during the first 6 months of treatment, (2) a nadir reached at 6–12 months, and (3) a continuous increase until radiological disease progression (or discontinuation of follow-up). In some patients (15/40, 38%), ctDNA became undetectable at some point during therapy despite the high sensitivity of the assay, with sustained ctDNA clearance associated with no risk of impending tumor progression. Conclusions: Serial analyses with a highly sensitive ctDNA test uncover the molecular trajectory of tumor response to first line AI+PAL. The presence of an early ctDNA nadir, followed with a later slow and continuous increase of ctDNA, prior to radiological progression, highlights the dynamic nature of ER+ HER2- mBC response to therapy. This approach can complement imaging-based disease monitoring, extends the clinical utility of ctDNA monitoring beyond individual mutations, and opens new perspectives of therapeutic interventions and treatment adaptation. Clinical trial information: NCT03079011 .

550 Background: Patients with node-positive HR+/HER2- early breast cancer are at high risk for relapse within 5 years of diagnosis, suggesting the potential need for treatment escalation. However, it is unclear which patients may experience worse recurrence-free outcomes and thus benefit from additional therapy. Ataraxis Breast (ATX) is an artificial intelligence (AI) test that integrates clinicopathologic variables with features extracted from whole-slide H&E images to estimate recurrence risk. Here, we perform a secondary analysis of the control arm of the UNIRAD trial, evaluating the ability of ATX to identify patients treated with standard-of-care therapy who may be candidates for treatment escalation. Methods: Clinical information and scanned H&E slides were sourced for 365 patients enrolled in the UNIRAD trial who were randomized to the control arm (standard-of-care therapy). ATX scores were generated using a locked model with pre-specified thresholds. No patients from UNIRAD were used in the training of ATX. Recurrence-free interval (RFI) was used as the primary endpoint. Kaplan-Meier estimators were used to predict the probability of meeting the RFI endpoint. To quantify relative differences in the hazard of experiencing an event contributing to the RFI endpoint associated with ATX scores, Cox proportional hazards models were fitted, from which hazard ratios (HRs) were estimated. The discriminative performance of ATX was evaluated using C-index. Results: Of the 365 patients randomized to the control arm of the UNIRAD trial with H&E slides available, 163 (45%) were classified as ATX low risk, and 202 (55%) as ATX high risk. Patients classified as ATX high risk had lower Kaplan-Meier-estimated probability of meeting the RFI endpoint (77%, 95% CI = 70-83%) than patients classified as ATX low risk (93%, 95% CI = 88-97%). Consistent with these findings, when modeled as a continuous variable, higher ATX scores were associated with a significantly higher hazard of an RFI-contributing event (HR = 1.57, 95% CI = 1.29-1.99, p-value < 0.001) and demonstrated strong discriminatory performance (C-index = 0.66, 95% CI = 0.59-0.72). This association remained significant after controlling for receipt of neoadjuvant therapy, tumor, and nodal stage (HR = 1.53, 95% CI = 1.05-2.23, p = 0.027). Conclusions: In the clinically homogenous UNIRAD trial cohort of patients with node-positive HR+/HER2- early breast cancer, ATX high risk patients treated with standard-of-care therapy had a significantly increased hazard of an RFI-contributing event. These findings suggest that AI-based risk stratification identifies biologically high risk patients who may derive benefit from adjuvant treatment escalation. Clinical trial information: NCT01805271 .

BACKGROUND:Adjuvant chemotherapy for hormone receptor-positive (HR+) breast cancer relies on taxanes, but existing tests do not identify which patients benefit from them. The SETER/PR index, a measure of endocrine-related transcriptional activity in HR + tumors, recently predicted benefit from paclitaxel when low (<0.75), but not for anthracycline-based therapy. We tested whether SETER/PR could predict benefit from docetaxel in node-positive, HR + patients enrolled in the PACS-01 trial (docetaxel after fluorouracil-epirubicin-cyclophosphamide (3FEC+3D) versus 6FEC). PATIENTS AND METHODS:SETER/PR index and Recurrence Score (RS) were obtained for 490 patients. SETER/PR was quantified using the QuantiGene Plex assay from RNA remaining after RS testing. Pre-specified analyses assessed SETER/PR as a continuous variable and using the predefined <0.75 cut point, as well as continuous RS and the >25 cut point. The primary endpoint was distant recurrence-free interval (DRFI). Predictive value was assessed using Cox models including biomarker, treatment arm, and interaction term. RESULTS:Continuous SETER/PR demonstrated significant interaction with treatment on DRFI (Pinteraction = 0.028), whereas predefined <0.75 cut point was not predictive (Pinteraction = 0.668). Exploratory analyses identified a cut point at 1.50 (Pinteraction = 0.013): patients with SETER/PR ≥ 1.50 had worse outcomes with 3FEC+3D versus 6FEC (HR 3.16, 95%CI 1.28-7.85), while outcomes were similar between arms when SETER/PR < 1.50 (HR 0.83, 95%CI 0.51-1.35). RS did not predict differential benefit, either continuously (Pinteraction = 0.670) or at the >25 threshold (Pinteraction = 0.534). CONCLUSION:Including sequential docetaxel (3FEC+3D) was less effective than continued anthracycline chemotherapy (6FEC) when breast cancer had high endocrine-related transcriptional activity (i.e., SETER/PR index ≥1.50). TRIAL REGISTRATION:PACS-01.

Background Breast cancers expressing low (1-9%) immunohistochemistry levels of estrogen and progesterone hormone receptors (HR), remain an uncertain category, being considered either as triple negative (TN) breast cancers or HR-positive (HR+) tumors across guidelines or approvals. Methods ESME is a National real-world cohort of all consecutive patients who initiated a first-line treatment for metastatic breast cancer (MBC) from year 2008 onwards in one of the 18 French Comprehensive Cancer Centers. We analyzed baseline data and outcomes from all patients with HER2-negative MBC and known HR expression levels. Our primary objective was to evaluate overall survival (OS) in HR-low MBC patients compared with those with TN and HR+ disease. Results Out of 30,459 patients in the ESME database who initiated an MBC treatment between 01/2008 and 01/2021, 19,109 were eligible for this analysis: 16768, 2113, 228 respectively with HR+, TN, and HR-low MBC. Median follow-up was 58.0 months (56.6-59.0).Median OS were 44.6 (43.8-45.5), 19.1 (15.5-22.4) and 15.7 (15.0-16.8) months in the HR+, TN, and HR-low groups, respectively. The multivariable analysis identified no difference in OS between HR-low and TN groups (Hazard Ratio 0.93, 95%CI 0.77-1.11). Median PFS under first line chemotherapy were 10.2 (9.9-10.6), 5.3 (5.1-5.6) and 5.1 (4.1-6.2) months for HR+, TN and HR-low groups, respectively. In the multivariable analysis, the HR-low group had a statistically poorer PFS compared to the TN group (Hazard Ratio 1.24, 95% CI 1.04-1.49). Conclusions In this large cohort, patients with HR-low MBC have the same dismal overall survival as those with TN MBC.

PURPOSE:Despite current standard-of-care endocrine therapy, distant recurrence remains a concern for patients with hormone receptor-positive (HR+)/HER2- early breast cancer (EBC). Understanding individual recurrence risk would aid in clinical decision-making. We used machine learning to identify risk factors and develop recurrence risk prediction models. EXPERIMENTAL DESIGN:Predictor variables were identified by gradient boosting and used to train models on a large, diverse real-world dataset of patients with stage I-III HR+/HER2- EBC obtained from the US-based, electronic health record-derived deidentified Flatiron Health Research Database. An elastic net-penalized Cox proportional hazards model was validated internally with real-world data and externally with data from the NATALEE trial of ribociclib in patients with HR+/HER2- EBC. Prediction and outcome concordance for distant recurrence and treatment effect were analyzed with Harrell's concordance index (C-index) and integrated Brier score; model performance over time was determined by dynamic AUC analysis. RESULTS:The model accurately predicted distant recurrence in the real-world cohort [n = 7,842; C-index: 0.85 (95% confidence interval, 0.8461-0.8598); integrated Brier score: 0.05 (95% confidence interval, 0.0443-0.0495)] over time (AUC >0.7 through 10 years); internal validation and sensitivity analyses confirmed model performance. External validation with the NATALEE nonsteroidal aromatase inhibitor alone arm yielded a lower but still discriminative performance (C-index: 0.66). Training on NATALEE data improved concordance (C-index: 0.70); the NATALEE-trained model predicted a 3.2% reduction in distant recurrence at 48 months with ribociclib treatment in the real-world cohort. CONCLUSIONS:A machine learning model was developed that accurately predicted distant recurrence in HR+/HER2- EBC. The identified predictor variables and developed models may aid in risk-based personalized treatment decision-making.

TPS645 Background: Historically, the treatment paradigm for hormone receptor-positive, HER2-negative early breast cancer (HR+ HER2− eBC) has relied on endocrine therapy (ET) and adjuvant chemotherapy. However, the absolute benefit of adjuvant chemotherapy is closely tied to baseline risk, being notably modest in intermediate risk eBC, while associated with significant short- and long-term toxicities. The phase III NATALEE trial demonstrated the efficacy of an adjuvant three-year treatment with ribociclib and ET in prolonging invasive disease-free survival (iDFS) in patients with high-risk HR+ HER− eBC. Contrarily to similar studies of CDK4/6 inhibitors in this setting, NATALEE included a group of patients with intermediate clinical risk (pT1-2 pN1, pT3-4 pN0 or pT2 pN0 with histological grade 3 or grade 2 with Ki67≥ 20%). These patients are usually treated with adjuvant chemotherapy based on the tumor clinicopathological characteristics or the results of a genomic signature. Nevertheless, the absolute benefit of adjuvant chemotherapy in these patients is uncertain (and likely reduced) in the context of an adjuvant treatment strategy that includes a CDK4/6 inhibitor. The NoLEEta trial aims at demonstrating that patients with intermediate-risk HR+ HER2− eBC treated with ribociclib and ET could be spared chemotherapy side effects while ensuring similar survival outcomes. Methods: NoLEEta is an international, randomized, open-label, non-inferiority phase III trial. Main inclusion criteria are: HR+ HER2− eBC after curative surgery, at intermediate risk of relapse (pT0-2 pN1, pT3-4 pN0, pT2 pN0 G3 or pT2 pN0 G2 with Ki67≥20%), eligible for adjuvant chemotherapy (per investigator decision, based on clinicopathological parameters or using a genomic signature). Eligible patients are randomized (1:1) to either receive ribociclib and ET (investigational arm without chemotherapy) or chemotherapy followed by ribociclib and ET (control arm). Primary endpoint is invasive breast cancer-free survival (iBCFS), defined in accordance with the STEEP system as the interval between randomization and the earliest occurrence of ipsilateral invasive breast tumor recurrence, local–regional invasive recurrence, distant recurrence, invasive contralateral breast cancer, or death from any cause. Secondary endpoints include invasive disease-free survival, distant disease-free survival, overall survival, interval and type of iBCFS events, incidence and severity of adverse events, and health-related quality of life. Enrollment in NoLEEta started in December 2025, with a target objective of 3902 randomized patients across 8 countries. One interim analysis is planned. Clinical trial information: NCT07237256 .

562 Background: A machine learning model was previously developed to predict distant recurrence (DR) in endocrine therapy–treated patients with HR+/HER2− EBC, with high accuracy achieved using 10 variables (Howard FM, et al. Clin Cancer Res . 2026). Here, optimal performance, based on the number and identity of variables, of recurrence models that include survival events (distant relapse–free survival [DRFS], overall survival [OS]) was determined. Methods: Retrospective data from patients with stage I-III HR+/HER2− EBC (diagnosed 1 January 2011 to 30 April 2024) were extracted from the Flatiron Health US electronic health record–derived database. Elastic net–penalized Cox proportional hazards–based machine learning models were developed with 2, 5, 10, 15, or 20 variables identified by gradient boosting to predict DR, DRFS, and OS; DRFS was defined according to STEEP criteria v2.0. Model performance was assessed using the C-index and Brier score (BS). Results: With modeling based on 7842 patients, DR prediction accuracy plateaued (C-index, 0.857; BS, 0.046) (Table) with 10 variables (N status, T status, tumor grade, Ki-67 score, age, time from diagnosis to surgery, percent estrogen receptor–positive cells, menopausal status [post-], Oncotype DX Recurrence Score, and percent progesterone receptor–positive cells). The DRFS (C-index, 0.740; BS, 0.089) and OS (C-index, 0.781; BS, 0.075) prediction models showed high accuracy with 5 to 10 variables, and accuracy continued to increase with up to 20 variables. In contrast to the DR prediction model, the DRFS and OS prediction models included functional status (ie, Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index) among the most impactful variables. Conclusions: DR model performance plateaued with 10 tumor-intrinsic variables. In contrast, optimal DRFS and OS prediction required expanding the model to 20 variables, including functional and comorbidity domains necessary to capture non-cancer competing risks critical for survival prediction in real-world populations, despite the modest statistical impact. The machine learning model for predicting DR, a reliable proxy for survival in HR+/HER2− EBC, is based on a lower number of risk factors that are commonly accessible in real-world clinics and has good accuracy. Model performance by outcome and number of variables. No. of variables DR (C-index a ) DR (BS b ) DRFS (C-index a ) DRFS (BS b ) OS (C-index a ) OS (BS b ) 2 0.812 0.044 0.667 0.093 0.611 0.081 5 0.849 0.046 0.718 0.092 0.770 0.075 10 0.857 0.046 0.736 0.089 0.774 0.075 15 0.858 0.046 0.737 0.089 0.776 0.076 20 0.851 0.047 0.740 0.089 0.781 0.075 a Concordance index; scores span from 0.5 to 1; 1 = perfect. b Brier score; scores span from 0 to 0.25; 0 = perfect.

BackgroundThe human epidermal growth factor receptor 2 (HER2)-targeted therapy trastuzumab deruxtecan has demonstrated significantly improved efficacy versus chemotherapy in HER2-low or -ultralow, hormone receptor (HR)-positive metastatic breast cancer (mBC) following endocrine therapy (ET). This study describes current real-world characteristics and outcomes for this population in France to inform optimized treatment sequencing, including the potential benefits of novel treatments.MethodsData were obtained from the Unicancer Epidemiological Strategy and Medical Economics (ESME) MBC database of adult patients with mBC. Patients were diagnosed with HER2-low, HR-positive mBC between 2008–2022 and initiated a chemotherapy-based regimen (index line of therapy [LOT]) after ≥1 qualifying line of ET. Real-world overall survival (rwOS) and progression-free survival (rwPFS) were assessed from the start of index LOT. ResultsAmong 326 patients selected, index LOT was third line (3L) or greater (“index 3L+ group”) for 202 (62.0%) patients and second line for 124 (38.0%) patients; 101 (31.0%) patients initiated index LOT after progression within 6 months of first-line ET + cyclin-dependent kinase 4/6 inhibitor (“rapid progressors”). Median rwOS (95% confidence interval [CI]) for the overall cohort, index 3L+ group, and rapid progressors was 23.1 (19.7, 27.5), 27.6 (22.7, 31.3), and 18.6 (14.3, 23.0) months, respectively. Median rwPFS (95% CI) for the overall cohort, index 3L+ group, and rapid progressors was 5.1 (4.8, 5.7), 5.2 (4.7, 6.0), and 5.6 (4.6, 6.3) months, respectively.ConclusionsThese real-world data suggest limited long-term efficacy of chemotherapy-based treatments for patients with ET-resistant HER2-low, HR-positive mBC, emphasizing high unmet need in this population.

OBJECTIVE:To evaluate outcomes of first-line ET + CDK4/6i for HR+/HER2 metastatic breast cancer (MBC) based on BRCA/PALB2 mutations status known at treatment initiation. METHODS AND PATIENTS:This cohort study included patients from 18 French comprehensive cancer centers treated with first-line ET and CDK4/6i between August 1, 2013, and December 31, 2023. Multivariable models including a Cox proportional hazard with a time-varying approach and landmark analyses at different timepoints (at the initiation of the first-line therapy and at 6 months after the initiation of the first line) assessed the association between germline and/or somatic BRCA and PALB2 genes alteration (categorized as "BRCA/PALB2m" (mutated) "BRCA/PALB2wt" (wild type), and "untested"), with progression-free (PFS) and overall survival (OS). RESULTS:Among 4283 eligible patients, baseline status was categorized as BRCA/PALB2m in 80 patients (1.9%), BRCA/PALB2wt in 467 patients (10.9%), and untested in 3736 patients (87.2%). Median follow-up was 43.7 months [95%CI, 42.6-44.9]. Median PFS was significantly shorter in BRCA/PALB2m patients (9.9 months [7.6-13.0]) compared to BRCA/PALB2wt (15.4 months [13.9-17.3]) and untested patients (18.3 months [17.6-19.3]). In the multivariable analysis ((including age, number of metastatic sites, presence of visceral metastases, de novo status, and tumor grade), BRCA/PALB2m carriers had a shorter PFS compared to BRCA/PALB2wt (adjusted HR [95% CI] 1.61 [1.24-2.09]; p < 0.001). Time-varying approach, landmark analysis at 6-months and propensity score matching analysis showed consistent results. CONCLUSIONS AND RELEVANCE:In this cohort, using a careful methodology, BRCA1/2 and PALB2 mutation carriers had reduced PFS with first-line ET + CDK4/6i compared to wild-type patients.

BackgroundOral mucositis/stomatitis is a common adverse event during cancer treatment that can disrupt oral functioning and adherence to treatment. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, has shown promise in treating solid tumors. It has been associated with oral mucositis/stomatitis in clinical trials for breast and lung cancer (TROPION program). Currently, there is a lack of formalized guidelines for managing Dato-DXd-associated oral mucositis/stomatitis. The present study employed a modified Delphi approach to establish expert consensus on preventing, diagnosing, monitoring, and treating oral mucositis/stomatitis secondary to Dato-DXd and to improve patient care and clinical outcomes.Materials and MethodsA four-stage modified Delphi study engaging 15 oncology experts from Europe and Canada was used to establish consensus on managing Dato-DXd-induced oral mucositis/stomatitis in lung and breast cancer patients. Experts were selected based on their roles as investigators in Dato-DXd clinical trials, including but not limited to TROPION-PanTumor01, TROPION-Lung01, TROPION-Lung05, and TROPION-Breast01, and their experience managing cancer treatment-associated oral mucositis/stomatitis. The Delphi process included an initial meeting, two anonymized surveys, an in-person consensus meeting, and virtual one-to-one sessions for absentees.ResultsExpert consensus was reached on recommendations for managing Dato-DXd-associated oral mucositis/stomatitis, and experts highlighted the importance of establishing guidance to improve patient quality of life and clinical outcomes. Key recommendations included prophylactic dexamethasone mouthwash, patient education, and behavioral changes. Early detection through self-checks and monitoring was emphasized, and recommended treatment strategies were tailored to oral mucositis/stomatitis severity. Treatment recommendations included dose modifications and discontinuation for severe cases.ConclusionsThis study offers expert guidance on managing Dato-DXd-associated oral mucositis/stomatitis, filling a crucial gap in patient care. Ongoing efforts to generate Dato-DXd-specific data will facilitate the creation of standardized, evidence-based protocols to improve patient safety and treatment outcomes.

1002 Background: In the primary analysis of the phase 3 TROPION-Breast02 study (NCT05374512), first-line Dato-DXd demonstrated statistically significant and clinically meaningful improvements in overall survival (OS; hazard ratio [HR]: 0.79 [95% confidence interval [CI]: 0.64–0.98]; p = 0.0291) and progression-free survival (PFS; HR: 0.57 [95% CI: 0.47–0.69]; p < 0.0001) compared with investigator’s choice of chemotherapy (ICC) in patients with locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option. Both median OS and PFS by blinded independent central review (BICR) were ≥5 months longer with Dato-DXd compared with ICC. Moreover, with Dato-DXd vs ICC, the confirmed objective response rate was more than double and median duration of response was > 5 months longer. The Dato-DXd safety profile was manageable and generally consistent with the known profile. Here we report additional efficacy endpoints. Methods: Adult patients with previously untreated locally recurrent inoperable or metastatic TNBC, for whom immunotherapy was not an option, were randomized 1:1 to Dato-DXd (6 mg/kg IV every 3 weeks) or ICC ([nab]-paclitaxel/capecitabine/eribulin mesylate/carboplatin). Dual primary endpoints were OS and PFS by BICR per RECIST 1.1; secondary endpoints included time to second progression or death (PFS2), time to first subsequent therapy or death (TFST), and time to second subsequent therapy or death (TSST). The planned sample size was approximately 600 randomized patients. A stratified log-rank test was used to analyze PFS2, TFST, and TSST. HRs and 95% CIs were estimated from a stratified Cox proportional hazards model. Results: A total of 644 patients were randomized (Dato-DXd: 323; ICC: 321). At data cutoff (25 Aug 2025), median study follow-up was 27.5 months and 53 (8.4%) patients remained on treatment (Dato-DXd: 45 [14.1%]; ICC: 8 [2.6%]). PFS2 was longer with Dato-DXd vs ICC: median 15.6 vs 11.8 months (HR: 0.61 [95% CI: 0.50‒0.74]). Both TFST and TSST were prolonged in the Dato-DXd vs ICC arm: median TFST was 10.9 vs 5.6 months with Dato-DXd vs ICC (HR: 0.49 [95% CI: 0.41‒0.59]) and median TSST was 16.7 vs 12.6 months (HR: 0.67 [95% CI: 0.55‒0.81]). Conclusions: In TROPION-Breast02, improvements in the secondary endpoints of PFS2, TFST, and TSST were observed for patients receiving Dato-DXd compared with ICC, consistent with the dual primary endpoints of OS and PFS by BICR. Alongside the manageable safety profile for Dato-DXd, these data further support Dato-DXd as the new first-line standard of care in this setting. Clinical trial information: NCT05374512 .

1030 Background: T-DXd is the standard second-line treatment for HER2-positive MBC with TTC being the preferred third-line option. However, the efficacy of TTC following T-DXd remains unclear. Here, we provide an updated and subgroup analysis of a French cohort comprising 101 patients who received TTC after T-DXd. Methods: We conducted a retrospective study across 12 French comprehensive cancer centers, including patients with HER2-positive MBC treated with TTC after T-DXd exposure. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS) and time to next treatment (TTNT). Results: A total of 101 patients who initiated TTC between August 2020 and December 2022 were included in the analysis. The median age was 56.4 years (range: 30.8–84.8). Patients had received a median of 4 prior MBC therapies (range: 2–15), which included pertuzumab (81%) and T-DM1 (93%). 82 patients (81%) experienced progression on T-DXd, while 19 discontinued due to toxicity or other reasons. The data cutoff date was December 1, 2024. For the whole population, with a median follow-up of 29.6 months (95% CI [26.0–34.0]), the median PFS was 4.7 months (95% CI [3.9–5.8]), the median TTNT was 5.2 months (95% CI [4.5–6.6]), and the median OS was 13.9 months (95% CI [12.4–19.0]). For the 86 patients who initiated TTC immediately after T-DXd, the median PFS and TTNT were 5.2 months (95% CI [4.4–6.4]) and 5.5 months (95% CI [4.7–7.2]), respectively. HR+ disease was identified in 71.3% (n=72) of the cohort, with 84.7% receiving TTC immediately post-T-DXd. With a median follow-up of 29.6 months (95% CI [25.1–NR]), the HR+ population had a median PFS of 4.1 months (95% CI [3.5–5.6]) and a median OS of 13.4 months (95% CI [12.3–19.0]). The median TTNT was 4.7 months (95% CI [4.0–6.3]). Among the 65 RECIST-evaluable HR+ patients, best response included progressive disease in 40%, stable disease in 29%, partial response in 29%, and complete response in 2%. With a median follow-up of 29.3 months (95% CI [26.0–NR]), the HR- population had a median PFS of 5.8 months (95% CI [4.4–10.5]) and a median OS of 17.5 months (95% CI [10.6–22.9]). The median TTNT was 6.0 months (95% CI [4.9–10.7]). Among the 24 RECIST-evaluable HR- patients, best response included progressive disease in 25%, stable disease in 38%, partial response in 33%, and complete response in 4%. Conclusions: This large retrospective cohort with extended follow-up highlights the efficacy of TTC in HER2-positive MBC patients previously treated with T-DXd. These findings support the role of TTC as a viable treatment option post-T-DXd and provide insights for optimizing therapeutic strategies in this setting.

BACKGROUND:Triple negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy (NAC) face high risk of recurrence. BREASTIMMUNE-03 trial evaluates the efficacy of nivolumab and ipilimumab combination compared to capecitabine as adjuvant treatment. METHODS:This multicentre, randomized open-label phase II trial included TNBC patients with Residual Cancer Burden (RCB) of class II-III after NAC and surgery, and allocated them to randomization (1:1) to receive nivolumab plus ipilimumab or capecitabine for 24 weeks. Randomization was stratified by center, ECOG performance status (PS) 0 or 1, and RCB Class. Primary endpoint was disease free survival (DFS), assessed in the intent-to-treat population. Safety analysis according to NCI-CTCAE V5.0 included all patients who received at least one dose of study drug. RESULTS:From July 2019 to October 2021, 95 patients were randomized to the nivolumab plus ipilimumab arm (NIVO + IPI n = 45), or to the capecitabine arm (CT n = 50). With a median follow-up of 34.3 (IQR 33-36) months, 39 events (relapse or death) were reported: 17 (38 %) for NIVO + IPI; 22 (44 %) for CT (HR 0.84, 95 %CI 0.45-1.59; log-rank test p-value 0.5938). 17 (38 %) patients in the NIVO + IPI arm prematurely discontinued treatment due to treatment-related adverse events (AEs), versus 7 (14 %) in the CT arm. CONCLUSION:A 6-month post-operative nivolumab plus ipilimumab treatment did not significantly improve DFS compared to capecitabine in TNBC patients with RCB II-III and resulted in increased immune-mediated AEs. Despite premature trial termination, our results do not support nivolumab plus ipilimumab adjuvant treatment in this setting. TRIAL REGISTRATION:NCT03818685.

Les métastases leptoméningées du cancer du sein se définissent par l’envahissement des leptoméninges et du liquide cérébro-spinal par des cellules tumorales. Autrefois associées à un pronostic très sombre et une survie d’à peine quelques semaines, leur prise en charge a profondément évolué. Les avancées thérapeutiques, comme l’introduction de thérapies ciblées et une meilleure compréhension de la physiopathologie des métastases leptoméningées, favorisent aujourd’hui un diagnostic plus précoce, grâce à des séquences IRM dédiées et une analyse du liquide cérébro-spinal optimisée. La classification EANO-ESMO distingue notamment les métastases leptoméningées de type I (cytologie positive) à plus mauvais pronostic, mais plus sensibles aux traitements intrathécaux, et les métastases leptoméningées de type II (cytologie négative ou incertaine) souvent plus réceptives aux approches locorégionales telles que la radiothérapie. Les données issues de larges cohortes rétrospectives soulignent l’importance des traitements combinés : thérapies systémiques, injections intrathécales, radiothérapie, ainsi que la prise en charge précoce des symptômes et des soins palliatifs. Cette approche multidisciplinaire améliore la survie médiane, atteignant désormais plusieurs mois, voire parfois au-delà de dix mois dans les métastases leptoméningées HER2+. Des essais cliniques novateurs, à l’image de l’essai multicentrique français ETIC-LM (NCT05800275) évaluant l’association de trastuzumab intrathécal, de tucatinib oral et de capécitabine orale, ouvrent de nouvelles perspectives. Bien que le pronostic reste sévère, ces progrès dessinent un avenir plus favorable, avec un meilleur contrôle de la maladie et une amélioration de la qualité de vie des patients atteints de métastases leptoméningées.

Background: Inflammatory breast cancer (IBC) is a rare and highly aggressive clinical entity requiring multimodal treatment, including neoadjuvant chemotherapy, mastectomy, and radiation therapy. With the advent of anti-HER2 agents, significant progress has been made in HER2-positive subtypes but the outcome remains unsatisfactory in HER2-negative IBC. Pembrolizumab in combination with neoadjuvant chemotherapy improves pathological complete response (pCR) and survival in stage II/III triple-negative breast cancer (TNBC) and has become standard of care in this setting. Pembrolizumab also improves pCR in high-grade, HER2-negative, and ER-positive stage II/III breast cancer. Yet, little is known about the specific impact of chemo-immunotherapy in IBC. Methods: We conducted a prospective, national, multicenter, randomized, phase II study evaluating the efficacy of pembrolizumab in HER2-negative IBC (NCT03515798). Patients aged ≥18 years with stage III disease were randomized (1:2) to receive neoadjuvant chemotherapy with epirubicin/cyclophosphamide (EC) +/-5FU x 4 followed by weekly paclitaxel × 12 (arm A) or the same regimen with pembrolizumab administered 3-weekly (arm B). Patients were then subjected to complete mastectomy and axillary lymph node dissection, prior radiation therapy. Randomization was stratified according to hormone receptor (HR) status (HR+, i.e. ER or PR >10%; TNBC, i.e. ER and PR <10%). Primary endpoint was central assessment of pCR rate, as defined as no residual invasive disease in breast and axilla (ypT0/is, ypN0), in arm B. Secondary endpoints included central pCR rate in arm A, local pCR rates and safety. Exploratory objectives included pCR rates according to HR status and PD-L1 expression, as evaluated by combined positive score (CPS). Results: From 29/08/2018 to 22/06/2022, 53 stage III, HER2-negative, IBC patients meeting eligibility criteria were randomized in arm A (n=20, including 9 HR+ and 11 TNBC) and arm B (n=33, including16 HR+ and 17 TNBC). All patients were female, median age was 52 (33-71) and 54 (26-73) in arm A and B, respectively. Histology was of no special type in 70% of patients in both arms. PD-L1 expression on baseline tissue was available in 43 patients: CPS was >10 in 17 (39%) patients, with a non-significant numerical difference between arms (50% and 33% in arm A and B, respectively), and was negatively associated with HR expression. Four patients came off the study before surgery: 3 in arm B (1 consent withdrawal, 2 progressive disease) and 1 in arm A (investigator decision). The central pCR rate in arm B (pembrolizumab) was 24%, 90%CI [12-41] (21%, 90%CI [6-47] in HR+ and 27%, 90%CI [10-51] in TNBC). In arm A (control), the central pCR rate was 35%, 90%CI [17-58] (29%, 90%CI [5-66] in HR+ and 40%, 90%CI [15-70] in TNBC). The pCR rates per local assessment were consistent with central evaluation. There was no significant association between PD-L1 expression and pCR in both arms. Grade >3 treatment-related adverse events (AE) were reported in 65% and 69% of patients (including Serious AE in 20% and 39%) in arms A and B, respectively. Pembrolizumab-related grade >3 AEs were noted in 30% of patients (including SAE in 12%). Immune-related AE included skin rash (n=1, grade 2), myocarditis (n=2, grade 1 and grade 2), adrenal insufficiency (n=2, grade 2 and grade 3), hepatitis (n=2, grade 2 and grade 3), thyroiditis (n=2, grade 2), and diabetes (n=1, grade 3). Conclusions: In HER2-negative IBC, pembrolizumab combined to neoadjuvant EC-paclitaxel chemotherapy induced a moderate pCR rate. Translational studies are ongoing to identify the determinants of therapeutic resistance. Innovative strategies including alternative cytotoxic backbones and novel immune-modulating agents are warranted in this aggressive disease. Citation Format: Alexandre de Nonneville, Florence Lerebours, Christophe Zemmour, Florence Dalenc, Christelle Levy, Thierry Petit, Marianne Leheurteur, Thomas Bachelot, Olivier Tredan, Sylvain Ladoire, Frédéric Viret, Leonor Lopez Almeida, Muge Kaya, Jean-Marie Boher, François Bertucci, Emmanuelle Charafe, Anthony Gonçalves. PELICAN-IPC 2015-016/Oncodistinct-003: a randomized phase II study of pembrolizumab in combination with neoadjuvant chemotherapy in HER2-negative inflammatory breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-10-10.

PURPOSE:Escalation of adjuvant systemic therapies (eg, with cyclin-dependent kinase 4 and 6 inhibitors) is now indicated for patients with clinically defined high-risk estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer, although it is unclear which will benefit from additional therapies. We developed and validated a prognostic clinicopathologic assay identifying a subpopulation of high-risk patients with good prognosis after standard adjuvant therapies, who may safely forgo treatment escalation. METHODS:We trained a Cox proportional-hazards model that integrates clinicopathologic variables with features derived from digitized hematoxylin-and-eosin-stained resection slides from a retrospective data set. The model assigns each patient to a low-risk or not low-risk group, reflecting their predicted risk of recurrence. Blind validation was successively performed on high-risk patients from the prospective trials CANTO (ClinicalTrials.gov identifier: NCT01993498) and UNIRAD (ClinicalTrials.gov identifier: NCT01805271). RESULTS:Built on data from 6,164 patients with ER+/HER2- early-stage breast cancer, this assay integrates four clinicopathologic variables, and 10 slide-derived features capturing tumor architecture, microenvironment, and proliferation. In the combined CANTO and UNIRAD trials (n = 633), 95.4% of the low-risk patients remained free of distant recurrence and death from breast cancer at 9 years, compared with 76.8% for the not low-risk group. Distant recurrence-free interval (subdistribution hazard ratio [HR], 0.21 [95% CI, 0.09 to 0.52]; P < .001), invasive disease-free survival (HR, 0.31 [95% CI, 0.16 to 0.60]; P < .001), and overall survival (HR, 0.35 [95% CI, 0.13 to 0.97]; P = .044) were all statistically significant. Multivariate analyses showed that the assay provided predictive information beyond clinicopathologic variables. Analytical validation showed robustness to data variability. CONCLUSION:The assay demonstrated robust performance in identifying a core group of patients with high-risk ER+/HER2- breast cancer for whom additional adjuvant treatment may be futile.